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Technical Briefs |
1 Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, Helsinki, Finland;2 Mehiläinen Oy Laboratoriopalvelut, Helsinki, Finland
aaddress correspondence to this author at: Division of Endocrinology, Department of Medicine, Helsinki University Central Hospital, FIN-00290 Helsinki, Finland; fax 358-9-47175798, e-mail matti.valimaki{at}hus.fi
Bone markers to monitor the efficacy of antiresorptive therapy of osteoporosis are of great value to clinicians. Considerable decreases in markers can be seen within 3 to 6 months after the start of an efficient treatment, with considerable increases in bone mineral density (BMD) being observed in 1 to 2 years (1)(2)(3). Decreases in marker concentrations reflect the patient’s compliance to treatment and, particularly for bisphosphonate therapy, the intestinal absorption of the drug, which may be poor. By indicating that the treatment is efficacious, biomarkers may also encourage the patient to continue therapy (4). Economic restrictions and the many bone turnover markers available make it challenging to choose the one that best serves these purposes and most reliably predicts fracture prevention. The most important consideration in practice may be to choose a marker that enables the clinician to make a clear distinction between responders and nonresponders to treatment.
The amino-terminal propeptide of type I procollagen (PINP) is liberated into the circulation during type I collagen formation, and its serum concentration reflects bone formation rate (5). Because of the coupling between bone resorption and formation, PINP shows promise as a sensitive indicator of the efficacy of antiresorptive therapy (6). Tartrate-resistant acid phosphatase (TRACP), an iron-containing 35-kDa enzyme, is produced in osteoclasts, beginning early in their development. TRACP has several known functions in the osteoclasts from which it is liberated into the circulation in active form (7)(8)(9). In addition to osteoclastic isoform TRACP5b, human serum contains another, differently glycosylated isoform, TRACP5a. Secreted TRACP5b activity, which can be measured specifically with a novel immunoextraction method (10), is believed to reflect bone resorption.
We compared serum PINP and TRACP5b as markers for distinguishing between responders and nonresponders to bisphosphonate treatment with alendronate or risedronate. The response was defined in terms of the least significant changes (LSC) in the markers. Sixty-nine postmenopausal women, 60 years of age or older, with osteoporosis (lumbar spine or total hip BMD T-scores –2.5 or lower, or both lumbar spine and total hip BMD T-scores –2.0 or lower) participated in the study, which was approved by the Ethics Committee of the Department of Medicine, Helsinki University Central Hospital. The study participants were a subgroup of a larger placebo-controlled trial in which changes in bone resorption and BMD were compared in patients receiving 70 mg of once-weekly alendronate and those receiving 5 mg of daily risedronate (11).
In the present study, 20 women received placebo, 26 risedronate, and 23 alendronate. All patients maintained a daily calcium intake of 1000 mg/day, and those with a baseline serum 25-hydroxyvitamin D concentration <15 µg/L received supplementation of 400 IU/day of vitamin D. Blood was sampled before and after treatment at 1, 3, 6, and 12 months. Serum samples were kept frozen at –70 °C until assayed for intact PINP and TRACP5b. PINP was determined by a competitive RIA with reagents (Intact PINP RIA) from Orion Diagnostica. The detection limit of the assay was 2 µg/L, and its intra- and interassay CVs ranged from 2% to 6%. TRACP5b activity was measured by an immunoextraction method with reagents (BoneTRAPTM) from Suomen Bioanalytiikka Oy. The limit of detection of this assay was 0.1 U/L, and the intra- and interassay CVs were 
6%.
The long-term intraindividual variability of the markers (CVi = SDi/meani) was calculated for placebo group participants from 5 measurements at 0, 1, 3, 6, and 12 months. From these CVis, the LSCs of the markers were calculated by the formula:
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which gives the LSC with a 95% confidence interval (12). The LSC for TRACP5b was 26.9% and for PINP was 28.3%. Responders with respect to changes in each marker were those who exhibited a decrease greater than or equal to the LSC. The change in a marker at each time point was expressed as percentage from the baseline value, using the formula:
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The changes in the markers over time were analyzed with repeated-measures ANOVA (Proc MIXED), with treatment group, time, and interaction of group and time as factors in the model. The natural logarithm transformation was used to achieve a normality assumption. The Fisher exact t-test was used to compare the number of responders between the treatment groups at different time points. The measure of agreement between responders, defined by TRACP5b and PINP, was compared by McNemar test for the whole study population and for each treatment group. All tests were performed 2-sided, with a 0.05 significance level, using the SAS® System (Ver. 8.02 for Windows).
Serum TRACP5b and PINP concentrations decreased in both treatment groups, although in the risedronate group TRACP5b changes were of borderline significance at 6 months (P = 0.091) and 12 months (P = 0.060; Fig. 1
). Over time, the alendronate group differed from the placebo group (P <0.0001) and from the risedronate group (P <0.0001) with respect to each marker, as did the risedronate group from the placebo group (P = 0.001 for TRAPC5b; P = 0.011 for PINP). In the whole study population (n = 69), the number of responders, based on the LSC, was higher at 1 month for TRACP5b than for PINP (P = 0.002; Table 1
); from that time point onward, the number of responders was higher for PINP than for TRACP5b (P <0.0001 to 0.008). The number of responders to risedronate identified by changes in PINP was significantly higher than the number identified by TRACP5b at 6 months (P <0.0001) and at 12 months (P = 0.008), as was the case for the responders to alendronate at 12 months (P = 0.031). At 1 month, more women were identified as responders to alendronate by TRACP5b than PINP (P <0.0001). At each time point, the number of responders was higher for alendronate than for risedronate (P <0.0001 to 0.005).
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In keeping with findings on urinary N-telopeptides of type 1 collagen in the primary study (11), alendronate suppressed serum TRACP5b and PINP more efficiently than did risedronate. Accordingly, in terms of the LSC, the percentages of responders to risedronate and alendronate were 12%–19% and 65%–78%, respectively, as determined with TRACP5b, and up to 54% and 96%, respectively, as determined with PINP.
Choosing bone markers to use in clinical practice is highly dependent on the antiresorptive treatment used. If a highly efficacious suppressant of bone turnover such as alendronate is used, several markers may be used to distinguish between responders and nonresponders. In the alendronate-treated patients in this study, TRACP5b identified responders after 1 month of treatment, but over time more responders (up to 96%) were identified by PINP, although differences between the markers remained small and statistically nonsignificant. The results were different for risedronate, the less suppressive effect of which was poorly indicated by TRACP5b but much better by PINP from 6 months onward. According to LSC, however, only 54% or fewer of patients treated with risedronate appeared to be responders. We came to a similar conclusion in our earlier study (13) of patients treated with clodronate for 2 years: 79% were responders by PINP, 34% by TRACP5b, and 40% by urine N-telopeptides of type 1 collagen when the LSC values of 32% (28% in the present study), 27% (27%), and 55%, respectively, were used.
Because the extent to which bone turnover should be suppressed by antiresorptive drugs to achieve the optimum balance between safety and efficacy is not known, the choice of bone markers for use in clinical practice is challenging. In risedronate-treated patients, the prevention of vertebral fractures was not improved by more advanced suppression of bone turnover (14), but this was not the case in alendronate-treated patients (15). Risk of adynamic bone disease, however, must be kept in mind when using efficacious bisphosphonates (16). We used the LSC values to compare the 2 markers. This method is statistically correct, but if sufficient fracture reduction and safety are achieved with only mild-to-moderate suppression of bone turnover, then changes in markers less than the LSC may be the aim of treatment, and LSC comparison would not be useful.
TRACP5b was inferior to PINP in revealing responders to treatment with risedronate or alendronate, although it detected the response to alendronate within 1 month. This quick response is not very useful in clinical practice, however, because measurements of bone markers are typically repeated after 3 to 6 months of treatment. In addition, measurement of PINP instead of TRACP5b is indicated for monitoring treatment with less efficacious suppressants of bone turnover.
Acknowledgments
This work was supported by a grant from Merck & Co., Inc.
References
The following articles in journals at HighWire Press have cited this article:
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  M. Kleerekoper and P. Camacho Monitoring Osteoporosis Therapy Clin. Chem., December 1, 2005; 51(12): 2227 - 2228. [Full Text] [PDF]
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) and the risedronate group (
) with respect to each marker (P <0.0001), and the risedronate group from the placebo group (P = 0.001 for TRACP5b and P = 0.0011 for PINP). In the alendronate group, changes from baseline for both markers were significant at each time point (P <0.0001). In the risedronate group, this was the case for PINP (P = 0.003 to <0.0001) and for TRACP5b at 1 (P <0.0001) and 3 months (P = 0.045).